The lungs are one of the few visceral organs regulated by afferent and efferent components of both the autonomic (vagal) and somatic nervous systems. Autonomic components involve vagal sensory receptors in the lungs and airways, and efferent innervation of airway smooth muscle or mucus secreting glands/cells. Somatic components necessary to even take a breath or defend the airways (cough) include the phrenic/diaphragm and accessory (intercostal, abdominal) motor systems. These afferent and efferent autonomic/somatic systems are coordinated by shared brainstem and spinal cord networks capable of selectively utilizing afferent and efferent components to produce regular breathing, or sporadic (triggered) airway protective behaviors (e.g. cough, laryngeal adductor reflex). The respiratory system consists of a multiscale sensorimotor control network that exhibits neuroplasticity. In this project we will investigate selected aspects of the respiratory system by: 1) electrical stimulation of the spinal cord or spinal sensory nerves, 2) transient perturbations in afferent feedback from cranial nerves, 3) intermittent hypoxia, 4) airway or systemic inflammation and 5) examination of clinical disorders that compromise breathing and airway defense. Several of the participating labs employ pharmacological, genetic and anatomical methods aimed at understanding vagal sensory pathways that regulate airway function. CRE mice will be used to delineate airway neuromodulator pathways from distinct vagal ganglia and their peripheral projections. We also will investigate neural mechanisms responsible for airway protection by elucidation of central circuits that give rise to the laryngeal adductor reflex. Neuroplasticity in afferent and efferent pathways of the phrenic sensorimotor system will be induced by electrical stimulation of spinal nerves and/or spinal cord. Our in vivo efforts will be unified by computational modeling of the sensory feedback and central neural system that controls respiratory function. These modeling efforts include the first simulations of the laryngeal adductor reflex and the NTS pathways that integrate airway mechanoreceptor and C-fiber feedback.